CH634574A5 - METHOD FOR PRODUCING 7- (2,3-DIHYDROXYPROPYL) -1,3-DI-N-PROPYLXANTHINE. - Google Patents

Description

The invention relates to a process for the preparation of the new compound 7- (2,3-dihydroxypropyl) -l, 3-di-n-propyl-xanthine, which as a bronchodilator, i.e. can be used as a bronchial muscle relaxant.

Theophylline (1,3-dimethylxanthine) of the structure:

is a naturally occurring xanthinal kaloid that was first described almost 55 years ago as a therapeutic agent for the treatment of asthma. However, its use as an oral bronchodilator only became popular in the late 1930s. It was quickly found, however, that although theophylline was effective, its lack of water solubility and the possibility of undesirable side effects impaired its suitability. Attempts have therefore been made continuously to improve the solubility of theophylline and to synthesize various derivatives thereof in order to increase the safety of therapy while maintaining the desired pharmacological properties.

Solubilization of theophylline has already been obtained by preparing addition compounds such as theophylline ethylenediamine (aminophylline), salts such as choline theophylline (oxtriphylline) or combinations with sodium acetate or sodium glycinate. However, these "soluble" theophylline preparations have not been able to significantly reduce the occurrence of undesirable side effects in the gastroin-testinal, cardiovascular, renal and in the central nervous system.

Attempts to modify the chemical structure of theophylline in order to obtain a compound with greater bronchodilator selectivity have also shown no detectable success. Although compounds with increased bronchodilator activity can be made, this is done at the expense of tolerance. The only synthetic derivative of theophylline that has found some therapeutic application is dyphylline, namely 7- (2,3-dihydroxypropyl) -1, 3-dimethyl-xanthine of the following formula:

Although dyphylline has an inherent high water solubility and few of the usual theophylline-like side effects, it has less bronchodilator activity than theophylline.

It can be seen from the activity of the dyphylline that the 2,3-dihydroxypropyl substitution in the 7-position of the basic theophylline base molecule markedly reduces the overall activity with regard to both the therapeutic activity and the 20 side effects. Roth et al. (J. Phar-macol. Exp. Ther. 121: 487, 1957) have observed the same phenomenon with 7-β-hydroxypropyl-1,3-dimethylxanthine, as well as Armitage et al. (Brit. J. Pharmacol. 17: 196, 1961) with a series of 7-hydroxyalkyl-6-thioxanthines. From 25 works by Roth et al. and McColl et al. (J. Pharmacol. Exp. Ther. 116: 343, 1956) has become known that 7-dihydroxypropyl substitution reduces activity more than 7-monohydroxypropyl substitution.

On the other hand, various authors have found that the pharmacological activity of theophylline can be increased by dialkyl substitution in the 1- and 3-positions. Kattus et al. (Bull. John Hopkins Hosp. 89: 1-8, 1951) have described that 1,3-diethyl, 1,3-dipropyl and 1,3-dibutylxanthine have extremely effective diuretic and emetic properties. However, no bronchodilator effect was found to be disadvantageous. By Armitage and al. A whole range of 1,3-dialkyl-substituted 6-thioxanthines were examined. Most of the compounds examined, including the 1,3-dipropyl derivative 40, had strong bronchodilator activity and were potent emetic agents.

It therefore appears from these literature reports that neither a 7-hydroxyallcyl nor a 1,3-dialkyl substitution of theophylline is suitable alone for improving the therapeutic effectiveness of the molecule as a bronchodilator. The former substituent reduces side effects but at the expense of activity, while the latter increases activity but at the expense of tolerance.

US Pat. No. 2,756,229 describes a series of substituted theophyllins which have both 7-monohydroxyalkyl and 1,3-dialkyl substituents. Such compounds of the formulas III and IV are specific:

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CH ^, - CH —CH.

fi

G H 3 7

7- (2-hydroxypropyl) -1,3-di-n-propylxanthine

III

3rd

634574

7- (3-hydroxypropyl) -1,3-di-n-propylxanthine.

According to this patent specification, it is said that these compounds are strong diuretics compared to theophylline and that they should be well tolerated at the same time. However, there is no information in this patent about the bronchodilator properties of these compounds.

Investigations by the applicant have shown that although compounds III and IV are more effective bronchodilators than theophylline, they are therapeutically unsuitable because of undesirable emetic, cardiovascular and CNS effects.

A compound that is comparable to theophylline as a bronchodilator, but has reduced side effects and increased water solubility, would therefore be an enrichment of the therapy.

A compound is now made available by the process according to the invention, characterized in the independent claims, for the preparation of the new compound 7- (2,3-dihydroxypropyl) -1,3-di-n-propyl-xanthine (indicated by the formula V) , which has bronchodilator properties that are comparable to those of theophylline, but at the same time has less adverse side effects.

CHo - CH-CH 'I I

N \ OH OH

n-CoH

On a molar basis, the new compound is comparable to theophylline as a bronchodilator, but is less active in terms of acute toxicity and undesirable cardiovascular, CNS, diuretic and oral emetic effects. Furthermore, it is considerably more water-soluble than theophylline.

The invention is explained in more detail below, for example, on the basis of the multi-stage method characterized in independent claim 2.

example

According to the above-mentioned method according to the invention, the new compound 7- (2,3-dihydroxypropyl) -1,3-di-n-propylxanthine is prepared by reacting 1,3-di-n-propyl-4-methylaminouracil with isoamyl nitrite and the 1,3-di-n-propylxanthine thus obtained is converted into the new compound by reaction with 1-chloro-2,3-dihydroxypropane.

The starting substance 1,3-di-n-propyl-4-methylamino

uracil itself can be obtained from n-propyl isocyanate in several stages by e.g. reacting n-propyl isocyanate with n-propylamine to 1,3-di-n-propylurea, reacting the 1,3-di-n-propylurea thus obtained with malonic acid to obtain 1,3-di-n-propylbarbituric acid, the 1, 3-di-n-propylbarbituric acid is reacted with phosphorus oxychloride and the 1,3-di-n-propyl-4-chlorouracil thus obtained is reacted with monomethylamine to give 1,3-di-n-propyl-4-methylamino-uracil.

In this example, the new compound 7- (2,3-dihydroxypropyl) -1,3-di-n-propylxanthine (V) is then prepared by the following reactions:

Starting substance:

CHi • CH2CH2-N = C = 0 + CH3CH2CH2NH2-1,3-di-n-propylurea (VI)

VI + H2C (COOH) 2 - 1,3-di-n-propylbarbituric acid (VII)

VII + PO Ch— 1,3-di-n-propyl-4-chlorouracil (VIII)

VIII + H2NCH3- * l, 3-di-n-propyl-4-methylaminouracil (IX)

New connection:

IX + isoamyl nitrite- * 1,3-di-n-propylxanthine (X)

X + CICH2CHOHCH2OH- 7- (2,3-dihydroxypropyl) -l, 3-di-n-propylxanthine (V)

The individual syntheses were carried out as follows:

A. Synthesis of 1,3-di-n-propylurea (VI):

1700 g (98.4%) of the product was prepared according to the method of Hayes et al., J. Agr. Food Chem., 17.1077 (1969) from n-propyl isocyanate (1020 g, 12 moles) and n-propylamine (708 g, 4.75 moles).

B. Synthesis of 1,3-di-n-propylbarbituric acid (VII): The synthesis was carried out according to the method of Goldner, Ann. Chem., 691, 142 (1966), whereby 1,3-di-n-propylurea (777 g, 5.38 mol), malonic acid (660 g, 6.34 mol), glacial acetic acid (1050 ml) and acetic anhydride (2160 ml) were used. 790 g (69.2%) of product with an mp of 77 to 80 ° C. were obtained. The NMR and IR spectra were consistent with the assigned structure.

Analysis for C10H16N2O3:

Calc .: C 56.58% H 7.59% N 13.20%

Found: C 56.50% H 7.66% N 13.08%.

C. Synthesis of 1,3-di-n-propyl-4-chlorouracil (VIII): The synthesis was carried out according to the Goldner method using 1,3-di-n-propylbarbituric acid (340 g, 1.6 mol) and phosphorus oxychloride (1920 ml). The crude product was distilled at 135 to 145 ° C / 0.05 mm, whereby pure VIII,

1400 g (95.1%), mp. 64 to 67 ° C was obtained. The NMR spectrum was consistent with the proposed structure.

D. Synthesis of 1,3-di-n-propyl-4-methylaminouracil (IX):

The production was carried out after a slight modification of the Goldner method. A solution of 1,3-di-n-propyl-4-chlorouracil (1400 g, 6.08 mol) in isopropyl alcohol (81) was treated with a solution of monomethylamine (about 400 g) in isopropanol (61). The mixture was stirred at room temperature overnight. It was then evaporated to dryness, treated with excess water, filtered, resuspended in water, filtered and air dried. In this way, pale white crystals with an mp of 108 to 110 ° C., 1240 g, (90.64%),

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receive. The IR and NMR spectra were consistent with the assigned structure.

Analysis for C11H19N3Q2:

Calc .: C 58.64% H 8.50% N 18.65%

Found: C 58.72% H 8.41% N 18.56%.

E. Synthesis of 1,3-di-n-propylxanthine (X):

The synthesis was carried out according to the Goldner method using a solution of 1,3-di-n-propyl-4-methylaminouracil (690 g, 3.06 mol) in ethanol (51), isoamyl nitrite (655 g, 5, 6 mol) and a saturated alcoholic hydrogen chloride solution (42 ml). The product was obtained as pale white crystals, 470 g (65%), mp. 201 to 205 ° C. The IR and NMR spectra were consistent with the proposed structure.

F. Synthesis of 7- (2,3-dihydroxypropyl) -1,3-di-n-propylxanthine (V):

A suspension of 1,3-di-n-propylxanthine (250.1 g, 1.06 mol) in water (300 ml) was treated with sodium hydroxide solution (50%, 85 ml). The mixture was filtered and evaporated to dryness. The residue obtained was treated with a solution of 1-chloro-2,3-dihydroxypropane (170 g, 1.59 mol) in isopropanol (700 ml). The mixture was stirred at reflux overnight, filtered and evaporated to dryness to give a brown gummy residue. The residue was dissolved in isopropyl alcohol and stirred with charcoal (20 g) overnight. The mixture was filtered, concentrated and allowed to crystallize overnight at 0 to -5 ° C. The crystals were filtered off, suspended in ether, refiltered and air dried to give white crystals (224 g, 72.17%), mp 88-91 ° C. Thin layer chromatography (5 ml of a 5% solution) on a silica plate developed in chloroform: methanol (9.5: 0.5) showed a spot. The IR and NMR spectra were consistent with the proposed structure.

Analysis for C14H22N4O4:

Calc .: C 54.18% H 7.15% N 18.05%

Found: C 54.39% H 7.32% N 18.03%

Solubility in water was 10% w / v and in chloroform about 31% w / v.

The new compound 7- (2,3-dihydroxypropyl) -1,3-di-n-propylxanthine (V), theophylline (I), 7- (2-hydroxypropyl) -1,3-di-n-propylxanthine (III ), 7- (3-hydroxypropyl) -l, 3-di-n-propylxanthine (IV) and dyphylline (II) were tested for their bronchodilator activity, acute toxicity and side effects according to the test methods described below.

The results obtained are summarized in Tables I and II.

Test methods:

A. Administration of the compounds and presentation of the values:

With the exception of theophylline, all compounds were administered as a free base or suspended in suitable aqueous vehicles. Theophylline was used in the form of aminophylline, i.e. the ethylenediamine addition compound. The ethylenediamine portion of the molecule is pharmacologically inert, but does provide solubility and uses

(Simons et al., S. Med. Journ. 68: 802, 1975). For the purpose of comparison, the aminophylline was believed to contain 80% by weight of free theophylline (Piafsky and Ogilvie, New England J. Med., 292: 1218, 1975). The final comparisons were always based on the calculated dose of theophylline. Because of the apparent differences in molecular weights, the compounds were compared on a molar basis rather than on absolute weight.

B. Bronchodilator examinations in guinea pigs:

1. Isolated trachea preparation:

The in vitro bronchodilator activity of each compound was determined with a spiral cut tracheal strip preparation of the guinea pig according to Constantine (J. Pharm. Pharmacol. 17: 384, 1965). Male guinea pigs (800 to 1200 g, Large Camm English Short Hair) were used to make three spiral tracheal strips from one animal. The strips were suspended in 50 ml tissue baths which contained a modified Krebs-Henseleit solution at 38 ° C and which were aerated with 95% O2 / 5% CO2. Pilocarpine HCl, 1 mg / 1, was added to the solution to maintain a fixed concentration and to promote rapid muscle recovery. A force displacement transducer (Grass FTQ, 03) was used to electronically record the muscle response. The concentration-relaxation relationship was determined for each compound by logarithmically increasing the bath concentration until maximum relaxation (100%) was observed. The tissues were washed between doses and allowed to recover for 30 minutes. A linear regression analysis of the percentage response against the logarithm of the bath concentration allowed the calculation of an inclination and the EC50 value (concentration which provides 50% of the maximum relaxation) for each connection. Each dose of each compound was tested at least six times.

2. Protection against histamine aerosol:

Bronchodilator activity was determined in vivo by measuring the ability of each compound to protect guinea pigs against constricting bronchospasm induced by exposure to histamine, as described by Armitage et al. (British J. Pharmacol., 16: 59, 1961). Adult male guinea pigs (270 to 600 g, Adult Camm English Short Hair) were kept individually in an inverted glass aquarium and continuously exposed to a finely atomized mist of 0.5% histamine diphosphate (made in a Devilbiss No. 40 atomizer) and 300 mm Hg compressed air . The period from the start of aerosolization to the occurrence of the final collapse or convulsions is referred to as the pre-convulsion time. This is relatively constant in the same animal. Pre-convulsion times were determined for each dose of each compound in at least six guinea pigs. Control pre-convulsion times were obtained 3 days before and 3 days after drug administration. The percent protection provided by each compound was calculated from the formula:

% Protection = (1-C / T) x 100

where C shows the average control pre-convection time and T the test pre-convulsion time after administration of the compound, each in sec. Animals with control pre-convulsion times longer than 2 min were not used. If the test pre-convulsion times are longer

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than 10 minutes, 100% protection was arbitrarily assumed. The dose of each compound that provided 50% protection (PDso) was calculated using the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 96:99, 1949).

The PDsu value of each test compound was determined after both antraperitoneal and oral administration. A minimum of 3 dose values and 6 animals per dose were used to obtain meaningful dose response values. The protective effect was measured 15 to 20 min after the intraperitoneal injection and 35 to 40 min after oral administration by a probe using a flexible plastic tube. The animals had to fast overnight before oral administration.

All compounds were administered in aqueous solution at concentrations that gave an appropriate volume dose. The guinea pigs were used 1 to 3 times, but none of the animals received the same compound twice in succession without a 3-day rest period between administrations.

C. Acute toxicity studies:

1. Intravenous and oral LD 50 values in mice:

The acute mean lethal dose (LDso) of each compound was determined in mice after both intravenous and oral administration. Swiss albino mice (Charles River) weighing 19.1 to 23.2 g were used. The sexes were represented equally in each dose group by at least 6 animals. Appropriate doses of each compound, dissolved in distilled water, were injected intravenously into the tail vein at a rate of 1 ml / min or administered orally with a loading needle. The acute responses and lethalities were observed and the corresponding LD> H values were calculated using the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 96: 99, 1949).

2. Oral LDso values in guinea pigs:

The acute mean lethal dose of each compound after oral administration was also determined in guinea pigs. Albino guinea pigs (Camm English Short Hair) with equally represented sexes and a weight range from 255 to 311 g were used for this. At least 6 animals per dose value were used. Oral administration was done with a flexible tube that was inserted into the stomach. All guinea pigs had to fast overnight. Because of their low solubility, it was necessary to suspend the compounds III and IV in 0.5% methyl cellulose. The other compounds were dissolved in distilled water. After the appropriate doses were administered, the acute responses and lethalities were determined. The LD 50 values were calculated using the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 96: 99, 1949).

D. Cardiovascular Exams:

1. Canine hind leg blood circulation preparation:

A total of 12 adult Mongrel dogs of each sex were used to investigate the direct intra-arterial expansion activity of the five test compounds. The animals were anesthetized with pentobarbital sodium, 30 to 35 mg / kg IV, and surgically prepared so that the arterial blood flow flowed into the femoral artery and that essentially the entire hind leg was controlled and kept constant. This was done with a variable speed peristaltic pump after proximal and distal cannulation of the femoral artery 7 Changes in arterial vascular resistance were reflected as changes in blood pressure measured with a T-tube on the distal side of the pump. The average systemic arterial pressure was also recorded for the contralateral femoral artery. Drug solutions dissolved in saline were injected into the arterial blood supply immediately before the blood entered the cannulated distal artery. Logarithmic increasing doses were administered at 10 min intervals. The answers were recorded.

2. Isolated rabbit heart preparation:

The cardiodynamic activity of each compound in the spontaneously beating isolated rabbit heart was determined in vitro by the Langendorff method, modified by Anderson and Craver (J. Pharmacol. Exp. Ther., 93: 135, 1948) (with the exception of dyphylline) .

After the aorta ascending from the extracted heart was attached to the device, the coronary arteries were continuously perfused with a vented Chenoweth solution (Chenoweth and Koelle, J. Lab. Clin., 31: 600, 1949) at a constant pressure peak and temperature was maintained at 38 ° C. The effects of logarithmically increasing doses of each compound were determined in terms of contractile force, heart rate and coronary current. The drugs were dissolved in minimal volumes of Chenoweth's solution and injected into the flow medium below the spout at 5-10 min intervals.

3. Examination of the intravenous cardiovascular effect in dogs:

Thirteen adult Mongrel dogs, each sex, weighing 16.7 to 25.0 kg, were used to compare the total intravenous cardiovascular activity of 5 test compounds. 3 dogs were used for each compound except for dyphylline (Compound II), which was tested on one animal.

The dogs were anesthetized with pentobarbital sodium, 30 to 35 mg / kg IV. They were fitted with an Endotra cheal tube and vented with a Harvard animal respirator pump. A femoral vein was cannulated for IV drug administration. The left common carotid artery was cannulated and the cannula tip was advanced into the aortic arch. A middle sternotomy was performed. Electromagnetic blood flow transducers (Biotronex) of appropriate size were placed around the ascending aorta and left in front of the descending corona artery. These procedural measures allow the following parameters to be continuously recorded or calculated:

a) mean arterial pressure (MAD); from the aortic cannula.

b) heart rate (HG); electronically from the pulsating ascending aortic flow.

c) Cardiac Delivery (CA); medium ascending aortic river.

d) myocardial contraction force (MKF); dQ / German the first derivative of the maximum aortic flow rate, also known as the peak acceleration of the aorta river.

e) stroke volume (SV); Quotient of CA / HG.

f) cardiac work (KA); Product from CA x MAD.

g) total peripheral resistance (GPW); Quotient from MAD / CA.

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h) coronary flow (ÏCF); middle left anterior descending coronary flow (LVA).

i) Coronary resistance (KW); Quotient of MAD / KF.

Logarithmically increasing doses of the respective compound were injected at 20 min intervals. Responses were measured 1, 2, 5, 10, 15 and 20 minutes after each dose. The mean response during this period was calculated. Theophylline (aminophylline), dyphylline (II) and compound V were used at both 20 and 80 mg / ml concentrations in distilled water. Compounds III and IV were used in concentrations of 10 and 30 mg / ml, respectively.

E. Dog Emetic Studies:

1. Intravenous ED:

Twelve adult mixed-breed dogs of each sex were used to determine the mean emetic dose (ED 50) of all five test compounds after intravenous administration. Appropriate doses of each compound were injected into groups of 4 animals. The animals were examined for emesis and signs of CNS stimulation. The onset, frequency and duration of emetic episodes were also recorded. The dogs that did not need to fast were allowed to rest for 2 days between doses. No animal received the same connection twice in a row. Previous research has shown that this protocol, which is acceptable for emetic tolerance to xanthines, does not occur and that a conditioned reflex over emesis over such a short period of time is difficult to establish (McColl et al., 1956). The EDso values were calculated using the method of Litchfield and Wilcoxon (1949).

2. Oral minimal emetic dose:

The minimum dose of each compound that caused emesis after oral administration was determined in a group of 5 adult mixed-breed dogs of each sex. Logarithmically increasing or decreasing (depending on the answer) doses of each compound were administered orally via a flexible gastric tube. The compounds were dissolved in distilled water at such concentrations that a 5 ml / kg constant volume dose was obtained. The animals had to fast overnight before administration. They were given a minimum rest of 3 days between doses and never received the same connection twice in a row. The onset, frequency and duration of emetic episodes, as well as signs of CNS stimulation, were also recorded.

F. Studies in mice on voluntary motor activity:

To attempt to quantitatively measure CNS activity, each compound was examined for its effect on voluntary motor activity in mice using the method of Dews (British J. Pharmacol., 8:46, 1953). Three cylindrical actophotometer cages were used simultaneously, each with 6 light beams and 6 photoelectric cells. Individual digital counters were connected to each activity cage. Male Swiss albino mice weighing between 19 and 24 g were used. The compounds were dissolved in distilled water and they were injected intraperitoneally in logarithmic doses in groups of 5 animals, using 3 groups per dose value. The

Control groups received saline. Immediately after the injection, the 5 mice were placed in the activity cage and the count was maintained for a 15 min period.

G. Diuretic examinations:

1. Acute oral examination in rats:

The oral diuretic effect of each compound was determined in rats after a modification of the Lipschitz et al. described method (J. Pharmacol. Exp. Ther., 79:97, 1943). Male Sprague-Dawley rats (car-worth) weighing 153-220 g were fasted overnight. Groups of 5 animals each were given three logarithmically graded doses of each compound, dissolved in saline, at a constant volume dose of 25 ml / kg via an oral delivery needle. The control animals received the same dose of saline only. The rats were then placed in individual metabolic cages and excluded from food and water for the rest of the experiment. At the end of the 6 hours, each rat was forced to urinate in the bladder by pulling on the base of the tail. The measured parameters included urine volume, pH and sodium and potassium excretion measured by atomic absorption analysis. The 6-hour values were averaged for each dose of the compound and for the control animals and compared accordingly.

2. Acute intravenous examination in dogs:

The acute intravenous diuretic activity of 3 logarithmically graded doses of each compound was assessed at *. female mixed breed dogs by a method similar to that of Ross and Cafruny (J. Pharmacol. Exp. Ther., 140: 125, 1963). The compounds were tested in 2 dogs each. The animals were initially hydrated orally with 30 ml / kg of water and then anesthetized with pentobarbital sodium, 30 to 35 mg / kg IV. A femoral vein was cannulated and a constant intravenous infusion of warm saline (3 ml / min) was started and continued through the experiment. The contralateral femoral vein was also cannulated for intravenous administration of the drug. The urine was collected directly from a bilateral ureter cannula. After a 20 minute control period, the first dose of the appropriate compound was injected and urine was collected at 20 minute intervals over a 1 hour period. This procedure was repeated for 2 additional doses of the same compound. Urine volume, pH, and sodium and potassium values were determined for each 20 minute collection period. The sums were obtained for the 1 hour period after each dose. The test results recorded as successive changes in each parameter were compared accordingly.

Results:

The test results are summarized in Table I, which expresses the pharmacological and toxicological activity over that of theophylline on a molar basis. Based on these values, Table II estimates the actual doses of each compound that are equivalent to the recommended therapeutic dose of theophylline and the extent of the major side effects that would be produced by this dose.

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Table I

Compilation of the relative molar activities

investigation

I II III IV

bronchodilator activity

Table II

Derived pharmacological effects at equivalent therapeutic doses in

IV

in vitro

(Tracheal strip)

1.00

0.16

1.86

2.05

0.99

in vivo i.p.

(Guinea pig)

1.00

0.12

3.26

0.94

1.56

in vivo, oral

( Guinea pig)

1.00

0.13

3.30

0.92

0.75

oral LDii / oral PD'- "

(Guinea pig)

1.00

2.00

5.43

3.57

3.75

Average

1.00

0.60

3.46

1.87

1.76

Acute toxicity and

Side effect activity

i.v. LDso (mice)

1.00

0.22

1.79

1.54

0.68

oral LDso (mice)

1.00

0.11

1.67

0.64

0.25

oral LDso

(Guinea pig)

1.00

0.06

0.61

0.26

0.20

Vasodilator; HBDZC

(Dogs)

1.00

0.06

0.76

1.06

0.40

in vitro; MKF, HG, CFd

(Rabbit heart)

1.00

_e

1.40

1.81

0.93

i.v. cardiovascular

(Dogs) f

1.00

0.36

1.16

2.02

0.91

oral emetic (dogs)

1.00

<0.50

251.00

6.00

0.50

i.v. emetic (dogs)

1.00

0.09

134.17

12.88

1.91

oral diuretic (rats)

1.00

0.71

7.29

1.48

1.05

i.v. diuretic (dogs)

1.00

0.26

0.50

0.45

0.59

i.p. CNS stimulation

(Mice)

1.00

0.18

1.73

0.48

0.30

Average

1.00

0.26

36.55

2.60

0.70

Therapeutic

Effectiveness8

1.00

2.31

0.09

0.72

2.51

Water solubility%

(Weight / volume)

0.8

33.0

1.0

3.0

10.0

Estimated bronchodilator for humans Dosisa (HBD): (mg / 70 kg) (mg / kg)

200 2.9

2353 33.6

99 1.4

347 5.0

299 4.3

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would cause the following side effects:

20 cardiovascular:

(i.v. dogs)

MADb (A -12 -20 mmHG)

HG (A BPM) +11 +11 25 MKF (% A) +17 - 5 CA (% A) + 7 -15 CAR (% A) - 5 -30 GPW (% A) -12 + 3 CF (% A ) +21 +10

30th

+21 +28 + 10 + 2 -15 + 8

-25

+80 +20 + 2 -26 - 5 + 4

- 5th

+ 7 + 15 + 6 + 2

- 9 + 17

Average

(12) (13) (13) (23)

(9)

35 emetic IV Dogs no none

(ED 50 mg / kg) (58) (900)

P.O. Dogs no none

(MED mg / kg) (128) (> 362)

40

severe moderate none

(0.7) (7.5) (53)

heavy no none

(0.8) (33) (442)

CNS activity:

i.p. Mice moderate

(% A) (+23)

severe moderate none (-60) (-17) (-1)

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I theophylline

II dyphylline

III 7- (2-Hydroxyprpyl) - i, 3-di-n-propylxanthine

IV 7- (3-hydroxypropyl) -1, 3-di-n-propylxanthine

V 7- (2,3-dihydroxypropyl) -1,3-di-n-propylxanthine a oral LDs ": average lethal dose b oral PDs": average protective dose c HBDZ: hind leg perfusion preparation d average relative activity for MKF, myocardial contractile force : HG heart rate: CF coronary flow.

e Dyphylline was not tested in this trial. "Mean relative activity of effects on arterial pressure, heart rate, contraction force, cardiac output, stroke volume, cardiac work, total peripheral resistance, coronary flow and coronary resistance.

g mean bronchodilator (therapeutic) activity divided by mean acute toxicity and adverse reaction activity.

diuretic activity:

i.v. Dogs mild moderate mild mild mild mild

50 '

I theophylline

II dyphylline

III 7- (2-hydroxypropyl) -I, 3-di-n-propylxanthine

IV 7- (3-hydroxypropyl) -1, 3-di-n-propylxanthine

V 7- (2,3-dihydroxypropyl) -1, 3-di-n-propylxanthine

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c

60 d

Dose: based on the recommended dose for theophylline and the relative activities in the bronchodilator tests.

MAD: medium arterial pressure; HG: heart rate; MCK: myocardial contraction force; CA: cardiac delivery; CAR: cardiac work; GPW: total peripheral resistance; CF: coronary flow.

EDso: mean emetic dose, MED: minimum emetic dose.

not definable.

Therapeutically effective bronchodilator, i.e. Bronchial muscle relaxing amounts of 7- (2,3-dihydroxy-propyl) -l, 3-di-n-propylxanthine can be administered to a living animal 65 suffering from reversible airway obstruction due to bronchoconstriction. The administration can be carried out by any measures and in any suitable form. White

634574 8

effective amounts of 7- (2,3-dihydroxy- general, the amount of 7- (2,3-dihydroxypropyl) -1,3-

propyl) -1,3-di-n-propylxanthine in a drug preparation di-n-propylxanthine, which is administered, about 1.0 mg to tung that usually for oral and parenteral consumption about 10.0 mg per kg body weight of the animal. Preferably used form are incorporated, and the amount administered is in the range of about 3.0 to be administered to the live carcass. Pharmaceuticals 7.0 mg per kg body weight of the animal.

preparations for oral administration, which are the further comparative tests with regard to oral

contain compound produced according to the invention, the administration of 7- (2,3-dihydroxypropyl) -1,3-di-n-propyl-in liquid form, e.g. as solutions, suspensions xanthine and of dyphylline in dogs have the following or syrups, or in solid form, e.g. as tablets, capsules give significant results:

or powder. The preparations for parenteral administration can be in the form of sterile aqueous solutions or 1. The compound produced according to the invention will be in suspensions. Advantageously, the pharmaceuticals can be easily absorbed after oral administration, the pharmaceutical preparations which contain the concentration of the medicament according to the invention in the plasma within a compound, increasing to a maximum in unit dose form one hour after administration. These are, with pharmaceutically acceptable carriers such as absorption rate and rate being very strong in dogs, glucose, lactose, gelatin, sucrose, stearates, similar to dyphylline.

Phosphates, water for injection and the like are used 2. After reaching the initial maximum pias. Buffers and preservatives as well as other maconcentrations also fall in the content of pharmaceutical auxiliaries according to the invention may be present. established connection in the plasma from slower

The amount of 7- (2,3-dihydroxypropyl) -1,3-di-n-propyl-20 as that of dyphylline (the biological half-value xanthine administered to the living carcass) times for the two compounds - plasma T1 / i - are naturally dependent on, among other things, the size of the animal according to the invention produced according to the invention more than 5 bodies, the respective animal to be treated, the hours of heaviness in contrast to about 2 hours for dyphylline).

degree of reversible obstruction of the airways due to the values obtained in these studies in relation to dyphylline bronchoconstriction and general health are very similar to those values that depend on the state of life of the living animal body. Any pharmaceutically effective amount that has been obtained in humans for dyphylline can be used. The plasma obtained in these examinations is sufficient to relax the bronchial muscle. The T '/ i value of more than 5 hours of the connection established according to the invention and in this way the obstruction of the airways is with the plasma T - V ^ - Raise or partially cancel value from 4 to. The dose can be compared on the basis of 30 6 hours, which is determined in published work on established medical methods. Clinical trials in humans have been reported.

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Claims (3)

634574 PATENT CLAIMS 1. Process for the preparation of 7- (2,3-dihydroxy-propyl) -l, 3-di-n-propylxanthine by reacting 1,3-di-n-propylxanthine with l-chloro-2,3-dihydroxypropane. 2. Process for the preparation of 7- (2,3-dihydroxy-propyl) -l, 3-di-n-propylxanthine, characterized in that 1,3-di-n-propyl-4-methylaminouracil is reacted with isoamyl nitrite and the 1,3-di-n-propylxanthine thus obtained is converted into the 7- (2,3-dihydroxypropyl) -1,3-di-n-propylxanthine by the process of claim 1. 3. 7- (2,3-dihydroxypropyl) -l, 3-di-n-propylxanthine prepared by the process according to patent claim 1. • CH, I 2 OH II